Ovarian cancer is the most lethal gynecologic cancer. Optimal cytoreductive surgery followed by platinum-based chemotherapy with or without bevacizumab is the conventional therapeutic strategy. Since 2016, the pharmacological treatment of epithelial ovarian cancer has significantly changed following the introduction of the poly (ADP-ribose) polymerase inhibitors (PARPi). BRCA1/2 mutations and homologous recombination deficiency (HRD) have been established as predictive biomarkers of the benefit from platinum-based chemotherapy and PARPi. While in the absence of HRD (the so-called homologous recombination proficiency, HRp), patients derive minimal benefit from PARPi, the use of the antiangiogenic agent bevacizumab in first line did not result in different efficacy according to the presence of homologous recombination repair (HRR) genes mutations. No clinical trials have currently compared PARPi and bevacizumab as maintenance therapy in the HRp population. Different strategies are under investigation to overcome primary and acquired resistance to PARPi and to increase the sensitivity of HRp tumors to these agents. These tumors are characterized by frequent amplifications of Cyclin E and MYC, resulting in high replication stress. Different agents targeting DNA replication stress, such as ATR, WEE1 and CHK1 inhibitors, are currently being explored in preclinical models and clinical trials and have shown promising preliminary signs of activity. In this review, we will summarize the available evidence on the activity of PARPi in HRp tumors and the ongoing research to develop new treatment options in this hard-to-treat population.
5516 Background: Patients with platinum-sensitive recurrent OC are often retreated with CbP due to limited treatment options. Ombrabulin (AVE8062), a combretastatin A4 analog, is a vascular disrupting agent that damages established tumor vasculature causing tumor necrosis and has synergistic antitumor activity with platinum agents in vivo (Cancer Sci. 2003;94:200). OPSALIN evaluated whether adding ombrabulin to CbP improves outcomes in patients with platinum-sensitive recurrent OC (NCT01332656; EFC10260). Methods: Patients (aged ≥18 yrs, ECOG PS ≤2) with platinum-sensitive measurable ovarian, fallopian tube, or primary peritoneum carcinoma after completion of one line of platinum-based chemotherapy received ombrabulin 35 mg/m² or Pbo plus CbP (AUC 5–6, 175 mg/m²) every 3 weeks. Randomization (1:1) was stratified by time of first disease recurrence (6–12 or >12 months). The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival, response rate (RR), and safety. An interim analysis after ~54 PFS events (60% of the target 90 PFS events) was planned. Results: From May 2011 to August 2012, 154 patients were randomized (n=77 in each group). Groups were balanced in terms of baseline characteristics. Overall, the median age was 56 yrs (range 34–79), 93% had ovarian primary tumors, and 54% had first disease recurrence >12 months. Planned interim analysis was performed after 53 PFS events (27 ombrabulin; 26 Pbo); median follow-up was 6.8 months. Ombrabulin did not improve PFS vs Pbo in any subgroup (global median 8.4 vs 10.4 months, respectively; HR 1.33; 60%CI 1.06–1.69). Overall, RR was 65% for ombrabulin and 71% for Pbo. Safety profiles were comparable; rates of grade 3–4 adverse events were 51% for ombrabulin and 41% for Pbo, with no particular safety signals. Conclusions: This interim analysis has suggested no safety concerns or efficacy advantage of adding ombrabulin to CbP in patients with platinum-sensitive recurrent OC. The study was discontinued due to limited probability of the ombrabulin arm showing PFS superiority at the final analysis. Study sponsored by Sanofi. Clinical trial information: NCT01332656.
